Pleiotropic Effects of PCSK9: Focus on Thrombosis and Haemostasis

The proprotein convertase subtilisin/keying 9 (PCSK9) is a serine protease that has gained importance in recent years as a drug target, mainly due to its effect on cholesterol metabolism in promoting the degradation of the low-density lipoprotein receptor (LDLR). However, this protease may also play an important role in lipid-independent reactions, including the process of thrombogenesis. Considering this, we reviewed the effects and implications of PCSK9 on platelet function and blood coagulation. PCSK9 knockout mice exhibited reduced platelet activity and developed less agonist-induced arterial thrombi compared to the respective control animals. This is in line with known research that elevated blood levels of PCSK9 are associated with an increased platelet reactivity and total number of circulating platelets in humans. Moreover, PCSK9 also has an effect on crucial factors of the coagulation cascade, such as increasing factor VIII plasma levels, since the degradation of this blood clotting factor is promoted by the LDLR. The aforementioned pleiotropic effects of the PCSK9 are important to take into account when evaluating the clinical benefit of PCSK9 inhibitors.